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MDR1 Mutations: A big deal...or not?

MDR1 Mutations and General Anesthesia in Small Animal Patient

Elizabeth M. Goudie-DeAngelis, DVM, MS, DACVAA



MDR1 mutation is more specifically a deletion of the MDR1 gene. Interestingly, the MDR name comes from the discovery of this mutation’s ability to confer multidrug resistance to cancer cells by extruding drugs from the cancer cell. Therefore MDR stands for multi-drug resistance and has traditionally been associated with Collie breeds, Sheepdog breeds, and mixed breeds representing these breeds. In addition, the mutation has been reported in Shepherds, McNabs, Wällers, Silken Windhounds, and Longhaired Whippets. In cats the mutation is uncommon but does occur. The gene is also known as ABCB1 and this gene codes for P-glycoproteins which utilize ATP to transport drugs across a variety of barriers in the body including the blood-brain barrier. In mice lacking the ABCB1 gene, there was a 100 fold increase in the amount of ivermectin within the brain.


Dogs or cats with the MDR1 mutation will have greater sensitivity to a variety of drugs, primarily the ivermectin-like drugs and several chemotherapeutic agents. In regards to general anesthesia, the mutation is often less of a barrier than many owners think. If there is a suspicion based on breed or historic anesthetic response, it is recommended that the individual is tested prior to anesthetic procedure. While many labs perform the testing, Washington State University is most commonly used due to their large volume of experience and research in the topic. In addition, they have a comprehensive list of drugs to be reduced or avoided in MDR1 mutated individuals. The degree of sensitivity to drugs depends on the patient’s expression; homozygous vs heterozygous with the homozygous being more sensitive.


Anesthetic or peri-anesthetic drugs to be avoided or dose modified include:

Dogs and cat specific:

Acepromazine

Butorphanol

Maropitant

Loperamide

Odansetron

Grapiprant

+/- Methadone

+/- Morphine

+/- Fentanyl

+/- Oxycodone


P-glycoproteins substrates the veterinary anesthetist may encounter:

Cyclosporin

Digoxin

Rivaroaxban

Tacrolimus

Colchicine

Vincristine

Vinblastine

Doxorubicin


The degree of signs are based on dose, rate, and gene expression. Neurologic signs including seizures, weakness, blindness, and disorientation. Other signs include vomiting.


When preparing to anesthetize a patient that the owner suspects has an MDR1 mutation, pre-testing should be performed. In a patient that has a known MDR1 mutation the owner should be advised about the risks of anesthesia and that many of our anesthetic agents have been found to be safe with a few exceptions. While morphine, methadone, and fentanyl have not been evaluated in veterinary MDR 1 patients they have been shown to be substrates in some invitro studies but invivo studies are inconclusive or show a relatively minimal effect with IV administrations. Therefore, regardless of protocol it is still worthwhile to advise the owner that the procedure should be done early in the day with plenty of time for recovery in case there is a delayed recovery related to the opioids.


When anesthetizing a patient with suspected MDR1 mutation or confirmed mutation, the anesthetist should avoid butorphanol and acepromazine while a lower dose of other opioids can be used. Cerenia, ondansetron, and Galliprant should be avoided. Other commonly used anesthetic drugs can be employed without concern for the MDR1 mutation.


In summary, while the MDR1 mutation can complicate an otherwise unremarkable anesthetic episode it is easy to determine how worried one needs to be (simple gene testing) and management requires avoidance or decreased dosing of a very select few drugs. Many of these at risk patients can be easily anesthetized with some planning.


References:

  1. https://prime.vetmed.wsu.edu/#:~:text=The%20MDR1%20genetic%20test%20offered,the%20dose%20of%20certain%20medications.

  2. Orzechowski KL, Swain MD, Robl MG, Tinaza CA, Swaim HL, Jones YL, Myers MJ, Yancy HF. Neurotoxic effects of ivermectin administration in genetically engineered mice with targeted insertion of the mutated canine ABCB1 gene. Am J Vet Res. 2012 Sep;73(9):1477-84. doi: 10.2460/ajvr.73.9.1477. PMID: 22924731.

  3. https://www.uptodate.com/contents/image?imageKey=DRUG%2F73326. Accessed 10.31.2023 at 13:21© 2023 UpToDate, Inc. and/or its affiliates

  4. Coluzzi F, Scerpa MS, Rocco M, Fornasari D. The Impact of P-Glycoprotein on Opioid Analgesics: What’s the Real Meaning in Pain Management and Palliative Care? International Journal of Molecular Sciences. 2022; 23(22):14125. https://doi.org/10.3390/ijms232214125






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